6-Oxo-3,6-dihydropyridine derivatives, preparation methods and medical applications thereof

Abstract

A 6-oxo-3,6-dihydropyridine derivative, a preparation method thereof and its application in medicine. Specifically, it relates to a 6-oxo-3,6-dihydropyridine derivative shown in general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, in particular, its use as a GLP-1 receptor agonist and its use in the preparation of a drug for treating and / or preventing diabetes.

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a 6-oxo-3,6-dihydropyridine derivative, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a 6-oxo-3,6-dihydropyridine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a GLP-1 receptor agonist in the treatment of diabetes. Background Art

[0002] Diabetes is a multi-cause metabolic disease characterized by chronic hyperglycemia, accompanied by disorders of sugar, lipid and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very old disease caused by an absolute or relative lack of insulin in the human body, which leads to an increase in blood glucose concentration, followed by large amounts of sugar excreted in the urine, and symptoms such as polydipsia, polyuria, polyphagia and weight loss.

[0003] Generally speaking, there are two types of diabetes. People with type I diabetes, or insulin-dependent diabetes, produce little or no insulin. Insulin is a hormone that regulates glucose utilization in the body. People with type II diabetes, or non-insulin-dependent diabetes, have plasma insulin levels that are equal to or higher than those of non-diabetic people. However, these people are resistant to insulin, which stimulates glucose and lipid metabolism in the main insulin-sensitive tissue cells, such as muscle, liver, and adipose tissue. Even increased plasma insulin levels cannot overcome the patient's significant resistance to insulin.

[0004] Insulin resistance is caused not only by a decrease in the number of insulin receptors, but also by insulin receptor defects, the mechanism of which has not yet been fully understood. Insulin resistance leads to the inability of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, and the inability to effectively inhibit adipose tissue lipolysis and the production and secretion of glucose in the liver.

[0005] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 exerts its corresponding effects by binding to its widely existing specific receptors. At present, the organs where GLP-1 receptors are clearly present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system. GLP-1 receptors may exist in the liver, adipose tissue and skeletal muscle. GLP-1 not only acts on β cells to promote insulin secretion, but also acts on α cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance and type II diabetes. However, there is a defect in the response of β cells to GLP-1 after eating. Under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Because the duration of action of the human body's own GLP-1 is very short (t1 / 2 <1.5 minutes for intravenous injection), the human body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0006] Peptide GLP-1 receptor agonists (such as liraglutide, exenatide, etc.) have the effect of reducing fasting and postprandial glucose and improving blood sugar in patients with type II diabetes. However, because the oral bioavailability of peptide GLP-1 is poor and inconvenient to take, it is highly desired to develop small molecule GLP-1 receptor agonists with good oral bioavailability.

[0007] Published patent applications for GLP-1 receptor small molecule agonists include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1 and WO2018056453A1, etc. Summary of the invention

[0008] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] G 1 , G 2 and G 3 The same or different, and each independently is CR 6 or N;

[0012] W 1 and W 2 are the same or different and are each independently selected from an O atom, a S atom, NR 7 and CR 8 R 9;

[0013] R 1 is selected from the group consisting of hydrogen, alkyl, heterocyclylalkyl, heteroarylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0014] R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0015] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0016] R 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0017] R 5are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0018] R 6 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0019] R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0020] R 8 and R 9 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0021] n is 0, 1, 2 or 3;

[0022] t is 0, 1, 2, or 3; and

[0023] p is 0, 1, 2, 3, 4 or 5.

[0024] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (I-1) or (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0025]

[0026]

[0027] in:

[0028] G 1 , G 2 , G 3 , W 1 , W 2 , R1 To R 5 , n, p and t are as defined in the general formula (I).

[0029] In some embodiments of the present disclosure, the compounds represented by the general formula (I), the general formula (I-1) and the general formula (I-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein G 1 , G 2 and G 3 The same or different, and each independently is CR 6 ; wherein said R 6 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0030] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1) and general formula (I-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein G 1 , G 2 and G 3 For CH.

[0031] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1) and general formula (I-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein W 1 and W 2 is an O atom.

[0032] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0033]

[0034] in:

[0035] R 1 To R 5 , n, p and t are as defined in the general formula (I).

[0036] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II-1) or (II-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0037]

[0038] in:

[0039] R 1 To R 5 , n, p and t are as defined in the general formula (I).

[0040] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 4 C 1-6 alkyl.

[0041] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 4 C 1-6 Preferably, the C 1-6 The alkyl group is methyl.

[0042] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 1 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 The alkylene group may be substituted by one or more substituents selected from the group consisting of alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic group.

[0043] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R 1 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 alkoxy, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic group or more substituents; preferably, the C 1-6 The alkyl group is substituted with a 3- to 6-membered heterocyclic group; more preferably, the C 1-6 The alkyl group is methyl, and the 3- to 6-membered heterocyclic group is oxetanyl.

[0044] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 2 are the same or different, each independently a hydrogen atom or a C 1-6 alkyl.

[0045] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 2 are the same or different and are each independently a hydrogen atom.

[0046] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 3 Selected from C 1-6 Alkyl groups, hydrogen atoms and halogens.

[0047] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R3 A hydrogen atom or a halogen.

[0048] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0049] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 5 are the same or different and are each independently halogen.

[0050] In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein p is 2.

[0051] In some embodiments of the present disclosure, the compounds represented by the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-2) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 is substituted by one or more substituents selected from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic group; R 2 are the same or different, each independently a hydrogen atom or a C 1-6 Alkyl; R 3 is a hydrogen atom or a halogen; R 4 C 1-6 Alkyl; R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0052] Table A Typical compounds of the present disclosure include, but are not limited to:

[0053]

[0054]

[0055] Another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0056]

[0057] in:

[0058] R w C 1-6 alkyl;

[0059] G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in the general formula (I).

[0060] Another aspect of the present disclosure relates to a compound represented by the general formula (IA-1) or (IA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0061]

[0062] in:

[0063] R w C 1-6 alkyl;

[0064] G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in the general formula (I).

[0065] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0066]

[0067] in:

[0068] Rw C 1-6 alkyl;

[0069] R 1 To R 5 , p, t and n are as defined in the general formula (IA).

[0070] Another aspect of the present disclosure relates to a compound represented by the general formula (IIA-1) or (IIA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0071]

[0072] in:

[0073] R w C 1-6 alkyl;

[0074] R 1 To R 5 , p, t and n are as defined in the general formula (IA).

[0075] Table B Typical intermediate compounds disclosed herein include but are not limited to:

[0076]

[0077]

[0078] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0079]

[0080] The compound of general formula (IA) undergoes hydrolysis reaction to obtain a compound of general formula (I),

[0081] in:

[0082] R w C 1-6 alkyl;

[0083] G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in the general formula (I).

[0084] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0085]

[0086] The compound of general formula (I) is subjected to chiral separation to obtain a compound of general formula (I-1) or (I-2),

[0087] in:

[0088] G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in the general formula (I).

[0089] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0090]

[0091] The compound of general formula (IIA) undergoes hydrolysis reaction to obtain a compound of general formula (II),

[0092] in:

[0093] R w C 1-6 alkyl;

[0094] R 1 To R 5 , p, t and n are as defined in the general formula (II).

[0095] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or (II-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0096]

[0097] The compound of general formula (II) is subjected to chiral separation to obtain a compound of general formula (II-1) or (II-2),

[0098] in:

[0099] R 1 To R 5 , p, t and n are as defined in the general formula (II).

[0100] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the compounds of the present disclosure shown in general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0101] The present disclosure further relates to the use of compounds shown in general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same in the preparation of drugs for stimulating GLP-1 receptors.

[0102] The present disclosure further relates to compounds of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2) and Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of pharmaceutical compositions for the treatment and / or prevention of type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetes and The invention relates to a method for preparing a medicament for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease or cardiovascular disease; wherein the type I diabetes is preferably idiopathic type I diabetes; the insulin resistance is preferably hepatic insulin resistance; and the cardiovascular disease is preferably selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease.

[0103] The present disclosure also relates to a method for agonizing a GLP-1 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2) and Table A or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0104] The present disclosure also relates to a method for treating and / or preventing type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia or insulin resistance; preferably, the method for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease or cardiovascular disease The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2) and Table A or its tautomers, mesomorphs, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

[0105] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2) and Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or pharmaceutical composition containing the same, which is used as a drug.

[0106] The present disclosure also relates to compounds shown in general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used as GLP-1 receptor agonists.

[0107] The present disclosure further relates to compounds represented by formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2) and Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and / or preventing type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes , gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia or insulin resistance; more preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease or cardiovascular disease; wherein the type I diabetes is preferably idiopathic type I diabetes; the insulin resistance is preferably hepatic insulin resistance; the cardiovascular disease is preferably selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease.

[0108] "Diabetic complications" are complications caused by diabetes or hyperglycemia, and they can be acute complexes or chronic complexes. The term "acute complexes" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary system infections, respiratory system infections, urinary tract infections), and "chronic complexes" include, for example, microangiopathy (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory nerve disorders, motor nerve disorders, autonomic nerve disorders), and gangrene. Major diabetic complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0109] "Coronary heart disease" includes myocardial infarction and angina pectoris.

[0110] "Dementia" includes, for example, Alzheimer's disease, (early onset dementia) EOD, vascular dementia, and diabetic dementia.

[0111] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compound of the present disclosure can also be formulated into a sustained release dosage form, such as a tablet, a hard or soft capsule, an aqueous or oily suspension, an emulsion, an injection, a dispersible powder or granules, a suppository, a lozenge or a syrup.

[0112] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid formulations. Suitable unit doses can be 0.1 to 1000 mg.

[0113] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0114] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0115] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0116] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0117] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0118] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0119] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0120] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0121] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0122] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0123] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0124] Terminology

[0125] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0126] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0127] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0128] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl can be substituted or unsubstituted, and when substituted, it is preferably one or more of the following groups, which are independently selected from one or more substituents in alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0129] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkynyl can be substituted or unsubstituted, and when substituted, it is preferably one or more of the following groups, which are independently selected from one or more substituents in alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0130] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8), and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.

[0131] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0132]

[0133] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-yuan / 5-yuan or 5-yuan / 6-yuan bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0134]

[0135] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0136]

[0137] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0138] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0139] The term "alkoxy" refers to -O-(alkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, its substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0140] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxidized (i.e., forming sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (e.g., 1, 2 and 3); more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

[0141] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, in which one atom (called spiral atom) is shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0142]

[0143] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0144]

[0145] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0146]

[0147] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0148] wait.

[0149] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0150] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0151]

[0152] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0153] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0154]

[0155] The heteroaryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being independently selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0156] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0157] The term "amino protecting group" is to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, etc. These groups can be optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro. The amino protecting group is preferably (trimethylsilyl)ethoxymethyl and tert-butyloxycarbonyl.

[0158] The term "hydroxy protecting group" refers to a group known in the art as being suitable for protecting a hydroxy group, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the hydroxyl protecting group. As an example, preferably, the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 Alkoxy substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy substituted C 1-4 Alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aromatic) acyl, such as formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 Aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10 The hydroxy protecting group is preferably a p-nitrobenzoyl group.

[0159] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0160] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0161] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0162] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0163] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0164] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0165] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0166] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0167] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0168] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0169] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0170] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0171] The term "hydroxy" refers to -OH.

[0172] The term "thiol" refers to -SH.

[0173] The term "amino" refers to -NH2.

[0174] The term "cyano" refers to -CN.

[0175] The term "nitro" refers to -NO2.

[0176] The term "oxo" or "oxo" refers to "=0".

[0177] The term "carbonyl" refers to C=O.

[0178] The term "carboxy" refers to -C(O)OH.

[0179] The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0180] The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure except that hydrogen is replaced by "deuterium" or "tritium", or by 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. Wherein the deuterated form of the compound is that each available hydrogen atom connected to the carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0181] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0182] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0183] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0184] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0185] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0186] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0187] As used herein, the singular form of "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0188] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0189] Synthesis method of the disclosed compound

[0190] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0191] Solution 1

[0192] The method for preparing the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt disclosed herein comprises the following steps:

[0193]

[0194] The compound of general formula (IA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (I)

[0195] in:

[0196] R w C 1-6 alkyl;

[0197] G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in the general formula (I).

[0198] Solution 2

[0199] The present invention discloses a method for preparing a compound represented by general formula (I-1) or (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0200]

[0201] The compound of general formula (I) is subjected to chiral HPLC separation to obtain a compound of general formula (I-1) or (I-2),

[0202] in:

[0203] G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in the general formula (I).

[0204] Option 3

[0205] The method for preparing the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt disclosed herein comprises the following steps:

[0206]

[0207] The compound of general formula (IIA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (II)

[0208] in:

[0209] R w C 1-6 alkyl;

[0210] R 1 To R 5 , p, t and n are as defined in the general formula (II).

[0211] Option 4

[0212] The present invention discloses a method for preparing a compound represented by general formula (II-1) or (II-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0213]

[0214] The compound of general formula (II) is subjected to chiral HPLC separation to obtain a compound of general formula (II-1) or (II-2),

[0215] in:

[0216] R 1 To R 5 , p, t and n are as defined in the general formula (II).

[0217] In the hydrolysis reaction, the alkaline reagent includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably lithium hydroxide or lithium hydroxide monohydrate.

[0218] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide and mixtures thereof. DETAILED DESCRIPTION

[0219] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0220] Example

[0221] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0222] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector) or THERMOUltimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0223] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0224] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0225] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0226] Chiral separations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0227] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0228] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm to 0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm to 0.5mm.

[0229] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200 to 300 mesh silica gel as the carrier.

[0230] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0231] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0232] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0233] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0234] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0235] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0236] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0237] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0238] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0239] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0240] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0241] Example 1

[0242] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 1

[0243]

[0244] first step

[0245] 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1c

[0246] Compound 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane 1a (287 mg, 0.84 mmol, prepared by the method disclosed in patent application WO2019239319A1 (see intermediate C4 on page 56 of the specification)), compound 6-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dioxolane Tert-butyl hydropyridine-1(2H)-carboxylate 1b (387 mg, 1.20 mmol, prepared by the method disclosed in patent application WO2011133733A1 (see intermediate 6-12 on page 67 of the specification)) was dissolved in 10 mL of dioxane and 2 mL of water, and sodium carbonate (266 mg, 2.51 mmol) and tetrakistriphenylphosphine palladium (97 mg, 83.94 μmol) were added, and stirred at 90°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to obtain the title product 1c (212 mg, yield: 55.2%).

[0247] MS m / z(ESI):403.9[M-55].

[0248] Step 2

[0249] 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-5,6-dihydropyridin-2(1H)-one p-toluenesulfonate 1d

[0250] Compound 1c (212 mg, 0.46 mmol) and p-toluenesulfonic acid monohydrate (219 mg, 1.15 mmol) were dissolved in 20 mL of ethyl acetate and stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude title product 1d (245 mg, p-toluenesulfonate), which was used directly in the next step without purification.

[0251] MS m / z(ESI):359.9[M+1].

[0252] Step 3

[0253] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 1f

[0254] Compound 1d (150 mg, 0.213 mmol, p-toluenesulfonate) was dissolved in 10 mL of toluene, sodium hydride (34 mg, 0.85 mmol) was added at room temperature, refluxed and stirred for 1 hour, cooled to room temperature, and compound (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 1e (63 mg, 0.213 mmol, prepared by the method disclosed in patent application WO2018109607A1 (see intermediate 23 on page 69 of the specification) was added), and stirred at room temperature for 20 hours. 10 mL of ice water was added to quench, extracted with ethyl acetate (20 mL×3), and the organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. After concentration under reduced pressure, it was purified by silica gel column chromatography with eluent system A to obtain the title product 1f (55 mg, yield: 41.7%).

[0255] MS m / z(ESI):617.9[M+1].

[0256] Step 4

[0257] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 1

[0258] Compound 1f (55 mg, 89 μmol) was dissolved in a mixed solvent of water, methanol and tetrahydrofuran (V:V:V=2:3:5), and lithium hydroxide monohydrate (37.4 mg, 0.89 mmol) was added and stirred at room temperature for 16 hours. The pH of the citric acid solution was adjusted to 5 to 6, and part of the solvent was evaporated under reduced pressure. 2 mL of N, N-dimethylformamide was added and dissolved, and then purified by high performance liquid chromatography (Waters-2767, chromatographic column: Boston Phlex Prep C18 5μm 30*150mm; mobile phase: water (10mM NH3HCO3); 26%-46% acetonitrile gradient elution within 20min, flow rate: 30mL / min; detection wavelength: 214&254nm) to obtain the title product 1 (35 mg, yield: 65.1%).

[0259] MS m / z(ESI):604.0[M+1].

[0260] 1H NMR (500MHz, DMSO-d6) δ12.75 (s, 1H), 8.30-8.23 (m, 1H), 7.82 (dd, 1H), 7.66 (d, 1H), 7. 62-7.55(m, 2H), 7.38(dd, 1H), 7.12-6.98(m, 2H), 6.98-6.91(m, 1H), 6.51(dd, 1H), 5.1 3-4.99(m, 2H), 4.88(d, 1H), 4.76(dd, 1H), 4.61(dt, 1H), 4.51-4.43(m, 1H), 4.36(dt, 1 H), 3.68 (t, 2H), 2.91-2.77 (m, 2H), 2.76-2.65 (m, 1H), 2.40-2.30 (m, 1H), 2.09 (s, 3H).

[0261] Example 2

[0262] 2-((4-(2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2

[0263]

[0264] first step

[0265] 4-Bromo-2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[d][1,3]dioxolane 2a

[0266] Compound 3-bromo-4-fluorobenzene-1,2-diol (10 g, 48.3 mmol, Wuxi Jiehua Pharmaceutical Technology Co., Ltd.), 4-chloro-2-fluoroacetophenone (9.17 g, 53.1 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), p-toluenesulfonic acid monohydrate (275 mg, 1.45 mmol) were dissolved in 100 mL of toluene and refluxed for 24 hours. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography with eluent system B to obtain the title product 2a (1.5 g, yield: 8.5%).

[0267] Step 2

[0268] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate 2b

[0269] The synthetic route of Example 1 was adopted, and the first step raw material 1a was replaced by raw material 2a to obtain the title product 2b (620 mg, yield: 64.4%).

[0270] MS m / z(ESI):422.1[M-55].

[0271] Step 3

[0272] 4-(2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[d][1,3]dioxolan-4-yl)-5,6-dihydropyridin-2(1H)-one p-toluenesulfonate 2c

[0273] The synthetic route of Example 1 was adopted, and the raw material 1c in the second step was replaced by the raw material 2b to obtain the title product 2c (946 mg, yield: 99.9%).

[0274] MS m / z(ESI):378.1[M+1].

[0275] Step 4

[0276] 2-((4-(2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 2d

[0277] The synthetic route of Example 1 was adopted, and the raw material 1d in the third step was replaced by the raw material 2c to obtain the title product 2d (55 mg, yield: 78.0%).

[0278] MS m / z(ESI):636.1[M+1].

[0279] Step 5

[0280] 2-((4-(2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2

[0281] The synthetic route of Example 1 was adopted, and the raw material 1f in the fourth step was replaced by the raw material 2d to obtain the title product 2 (26 mg, yield: 53.1%).

[0282] MS m / z(ESI):622.3[M+1].

[0283] 1H NMR (500MHz, DMSO-d6) δ12.75 (s, 1H), 8.26 (d, 1H), 7.82 (dd, 1H), 7.69 (d, 1H), 7. 63-7.55(m, 1H), 7.38(dd, 1H), 7.01(dd, 1H), 6.84-6.71(m, 2H), 6.18(s, 1H), 5.18 -5.00(m,2H),4.90(dd,1H),4.82-4.71(m,1H),4.62(dd,1H),4.51-4.43(m,1H),4 .34(dd, 2H), 3.68(dd, 2H), 2.86-2.66(m, 1H), 2.42-2.30(m, 2H), 2.06(d, Hz, 3H).

[0284] Example 3

[0285] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 1-A

[0286] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 1-B

[0287]

[0288]

[0289] Compound 1 (161 mg, 0.27 mmol) was subjected to chiral separation (separation conditions: chiral separation column CHIRALPAK IG20*250 mm, 5 μm, mobile phase: hexane / EtOH (0.1% TFA) = 70 / 30 / (V / V), flow rate: 20 mL / min), and the corresponding components were collected and freeze-dried to obtain the title products 1-A (45 mg) and 1-B (46 mg).

[0290] Single configuration compound 1-A (shorter retention time):

[0291] MS m / z(ESI):604.1[M+1].

[0292] 1H NMR (500MHz, DMSO-d6) δ12.48-12.88(brs, 1H), 8.20-8.30(m, 1H), 7.82(dd, 1H), 7.66(d, 1H), 7.51-7.63(m, 2H), 7.37(dd, 1H), 7.00-7.10(m, 2H), 6.89-6.97(m, 1H), 6.49(s, 1H), 4 .96-5.12(m,2H),4.87(d,1H),4.76(dd,1H),4.56-4.65(m,1H),4.41-4.50(m,1H),4.36(d t, 1H), 3.68 (t, 2H), 2.74-2.94 (m, 2H), 2.65-2.73 (m, 1H), 2.30-2.39 (m, 1H), 2.08 (s, 3H).

[0293] Chiral HPLC analysis: retention time 6.213 minutes, chiral purity: 100.0% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: hexane / EtOH / TFA=95 / 5 / 0.1 (V / V / V), flow rate: 1.0 mL / min).

[0294] Single configuration compound 1-B (longer retention time):

[0295] MS m / z(ESI):604.1[M+1].

[0296] 1 H NMR (500MHz, DMSO-d6) δ12.58-12.81(brs, 1H), 8.23-8.30(m, 1H), 7.82(dd, 1H), 7.67(d, 1H), 7.54-7.64(m, 2H), 7.37(dd, 1H), 7.00-7.12(m, 2H), 6.89-6.98(m, 1H), 6.50(s, 1H), 4 .98-5.12(m,2H),4.87(d,1H),4.76(dd,1H),4.56-4.66(m,1H),4.43-4.50(m,1H),4.36(d t, 1H), 3.68 (t, 2H), 2.77-2.89 (m, 2H), 2.67-2.73 (m, 1H), 2.32-2.38 (m, 1H), 2.08 (s, 3H).

[0297] Chiral HPLC analysis: retention time 8.280 minutes, chiral purity: 100.0% (chromatographic column: CHIRALPAK IG150*4.6 mm, 5 μm; mobile phase: hexane / EtOH / TFA=95 / 5 / 0.1 (V / V / V), flow rate: 1.0 mL / min).

[0298] Biological evaluation

[0299] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[0300] 1. Test Purpose

[0301] The purpose of this experiment is to test the agonist activity of compound molecules on GLP-1 receptors. 50 The size of the molecule is used to evaluate the in vitro activity of the molecule. TM Luciferase Assay System (ONE-Glo TM Luciferase Assay System, Promega, E6110). Under the action of compound molecules, the downstream signaling pathway of GLP-1R is activated, causing the cAMP level to increase. The binding of cAMP to CRE can initiate the transcriptional expression of the luciferase gene downstream of CRE. The luciferase reacts with its substrate to emit fluorescence. Through ONE-Glo TM The fluorescence signal measured by the reagent reflects the activity of the compound in stimulating the GLP-1 receptor.

[0302] 2. Experimental Methods

[0303] Construction of CHO-K1 / CRE-luc / GLP-1 receptor stable transfection cell line (GLP-1 receptor plasmid self-constructed; CRE-luc plasmid Promega E8471). CHO-K1 / CRE-luc / GLP-1 receptor cells were digested, centrifuged and resuspended, the single cell suspension was mixed, and the live cell density was adjusted to 2.5×10 with cell culture medium (DME / F-12+10% FBS). 5 cells / ml, 90 μL / well was added to a 96-well cell culture plate (Corning, #3903), and the culture plate was cultured in an incubator for 16 hours (37° C., 5% CO 2 ).

[0304] Dissolve the compound in DMSO and prepare a storage solution with an initial concentration of 20mM. The starting concentration of the small molecule compound is 0.2mM, dilute 3 times, dilute 10 points, and the 11th point is DMSO. Take another 96-well plate, add 95μL of cell culture medium (DME / F-12+10% FBS) to each well, then add 5μL of the sample to be tested at different concentrations to each well, mix well, and then add 10μL / well of the sample to be tested at different concentrations to the cell culture plate, and duplicate each sample. Incubate the culture plate in an incubator for 6 hours (37°C, 5% CO2). Take out the 96-well cell culture plate and add 100μL ONE-Glo to each well. TM Reagent, incubate at room temperature for 10 minutes, and measure chemiluminescence using an ELISA reader (EnVision 2105, PE).

[0305] 3. Data Analysis

[0306] The data were processed and analyzed using Microsoft Excel and Graphpad Prism 5. The EC values ​​of the compounds were obtained. 50 The results are shown in Table 1 below.

[0307] Example No. <![CDATA[EC 50 (nM)]]> Emax% 1 0.93 97 2 0.86 104 1-B 0.33 104

[0308] Conclusion: The compounds disclosed in the present invention have good agonist activity on GLP-1 receptor.

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof: in: G 1 , G 2 and G 3 The same or different, and each independently is CR 6 ; W 1 and W 2 is an O atom; R 1 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is substituted with a 3- to 6-membered heterocyclic group; R 2 are the same or different and are each independently selected from a hydrogen atom or C 1-6 alkyl; R 3 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; R 4 C 1-6 alkyl; R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; R 6 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; n is 0, 1, 2 or 3; t is 0, 1, 2, or 3; and p is 0, 1, 2, 3, 4 or 5.

2. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G 1 , G 2 and G 3 For CH.

3. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof: in: R 1 To R 5 , n, p and t are as defined in claim 1.

4. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II-2), or a pharmaceutically acceptable salt thereof: in: R 1 To R 5 , n, p and t are as defined in the general formula (I).

5. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 It is methyl.

6. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group, wherein the methyl group is substituted by an oxetanyl group.

7. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 A hydrogen atom.

8. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom or a halogen.

9. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 are the same or different and are each independently halogen.

10. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from:

11. A compound represented by the general formula (IA), or a pharmaceutically acceptable salt thereof, in: R w C 1-6 alkyl; G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in claim 1.

12. The compound represented by the general formula (IA) according to claim 11, or a pharmaceutically acceptable salt thereof, which is selected from:

13. A method for preparing the compound represented by general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound of general formula (IA) undergoes hydrolysis reaction to obtain a compound of general formula (I), in: R w C 1-6 alkyl; G 1 , G 2 , G 3 , W 1 , W 2 , R 1 To R 5 , p, t and n are as defined in claim 1.

14. A pharmaceutical composition comprising the compound represented by general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

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